Bioterrorism with variola virus is of immense concern because (a) virtually the entire world population is susceptible since routine vaccination was discontinued; (b) there are no treatments; (c) the virus in aerosol form is stable; (d) the virus is transmissible person-to-person; and (e) infection results in high morbidity and mortality. Vaccination with vaccinia virus (VV) was a key factor in eradicating smallpox. The necessity to vaccinate an at-risk population with W is central to preparing for the potential threat of smallpox bioterrorism. However recognized complications of vaccinia vaccination, especially in immunocompromised hosts, pregnant women, and infants impose serious limitations of this strategy. In past vaccination efforts, such complications were treated in the U.S. with human vaccinia immune globulin (VIG) obtained from W immunized people. Current stocks of VIG are low, and while new stocks are being generated, there are still serious drawbacks to relying on a blood product. Consequently, there is a critical need to develop therapeutic interventions to counter complications from the current vaccine and to develop a safer vaccine. As part of the mid-Atlantic Regional Center of Excellence in Biodefense & Emerging Infectious Diseases, our poxvirus research project's hypothesis is that vaccine candidates and new therapies can be developed by understanding and targeting poxvirus proteins recognized by the humoral and innate immune system. To do this we will: 1. Develop a subunit vaccine against smallpox (variola) virus (Cohen/Eisenberg/Friedman, U. Penn) 2. Identify new targets of neutralizing antibody (Isaacs, U. Penn) 3. Identify the targets of VIG using a proteomics approach (Lambris, U. Penn) 4. Develop an ectromelia virus challenge system in the mouse as a model of smallpox pathogenesis and prevention (Braciale, U. Virginia)